The present invention relates to a method of treating tumors in immune-privileged sites.
Cancer is presently the second leading cause of death in developed nations. Despite research that has revealed many of the molecular mechanisms of tumorigenesis, few new treatments have achieved widespread clinical success in treating solid tumors. The mainstay treatments for most malignancies thus remain gross resection, chemotherapy, and radiotherapy. While increasingly successful, each of these treatments still causes numerous undesired side effects. The primary cause of this is that none of these conventional methods specifically targets only diseased cells. For example, surgery, that can remove the primary tumor but not widespread metastasis, results in pain, traumatic injury to healthy tissue, and scarring. Radiotherapy and chemotherapy cause nausea, immune suppression, gastric ulceration and secondary tumorigenesis, and in the case of brain cancers in most cases chemotherapy does not penetrate the blood brain barrier (BBB).
In an effort to develop techniques to more specifically target diseased cells, progress in tumor immunology has led to the discovery of antigens that are preferentially or specifically expressed on cancer cells. These tumor-associated antigens (TAA) or tumor-specific antigens (TSA) have been used as antigenic agents in cancer vaccines designed to stimulate an immune response selectively directed against cancer cells expressing such antigens. See, Tumor Immunology: Immunotherapy and Cancer Vaccines A. G. Dalgleish and M. J. Browning, ods., Cambridge University Press, 1996; Immunotherapy in Cancer, M. Gore and P. Riches, eds., John Wiley & Son Ltd., 1996; Maeurer et al., Melanoma Res., 6:11-24 (1996).
Tumor cells have also been genetically modified to secrete various cytokines, including interleukin 2 (IL-2), IL-8, IL-4, IL-6, gamma-interferon (IFN-γ), and granulocyte-macrophage colony stimulating factor (GMCSF) and have successfully been used in cancer vaccines.
Although tumor vaccines are known to generate potent immune responses against tumors outside the central nervous system (CNS), established tumors within the CNS have failed to respond to such forms of systemic immunotherapy.
The CNS has been shown to accept allografts and xenografts that are otherwise immunologically rejected outside the CNS and thus has been considered an “immunologically privileged” site both historically [Murphy, J. B., and E. Sturm. 1926, Rockefeller Inst. Med. Res 21:183]) and more recently [Tjuvajev, J., et al., (1995) Cancer Res. 55, 1902-1910].
Although being surveyed by most cells in the immune system, the CNS is surveyed less per organ weight. Lymphocytes are found in low numbers in the CNS of healthy humans or animals, and following activation and entry into the brain, T cells encounter a suppressive cytokine environment, or are driven to apoptosis by FAS-FAS-L interactions.
Tumors in the brain are either ignored by the immune system or their growth is insufficiently controlled to prevent intracerebral growth. Immunotherapeutic modalities that were shown effective in treatment of cancers such as melanoma outside the CNS have failed to prevent tumor relapses inside the CNS [Mitchell, M. S. 1989. J Clin Oncol 7:1701]. Some modes of immunotherapy for brain originating tumors in rats even had negative effects on the clinical outcome [Graf, M. R. et al 2003. J Neuroimmunol 140:49].
The various mechanisms limiting immunoreactivity in the brain are incompletely understood, but likely include distinctive anatomic features such as the absence of conventional draining lymphatics, the presence of the blood-brain barrier, limited antigen presentation by microglia and astrocytes and their unique functionality as antigen presenting cells, Fas/Fas-L induced apoptosis of lymphocytes and TGF-β mediated cytokine shift.
Notwithstanding, the immune privileged status of the CNS is not absolute. In experimental allergic encephalomyelitis (EAE) a peripheral immunization with myelin basic protein (MBP) elicits CNS demyelination [Kalman, B., and F. D. Lublin. 1993. Curr Opin Neurol Neurosurg 6:182], suggesting that a systemic effector response can result in a specific immunoreactivity against antigens residing in the CNS. This notion was supported by observations that an effective anti-tumor response in the CNS can be generated through the use of cytokine-gene modified tumor cell vaccines [Sampson, J. H., et al., 1996. Proc Natl Acad Sci USA 93:10399; Chen, Y., T. et al., 2002, Blood 100:1373] or the transfer of antigen-specific CD8 Cytotoxic T lymphocytes (CTL) [Peng, L., et al 2000. J Immunol 165:5738].
U.S. Pat. No. 6,207,147 teaches an allogenic (histologically incompatible, non-autologous) adoptive transfer of lymphocytes to the patient for the reduction of brain tumors. The lymphocytes are stimulated with tumor cells to provide for their activation. The tumor cells alone are not taught as a method of treating tumors.
The reasons underling rarity of detectable systemic metastases of primary brain tumors is unknown. Approximately 10 cases of spontaneous metastasis of unresected primary GBM were reported in the literature, while the rest of the cases, amounting to less than 0.5% of the patients occurred following the resection of the primary CNS tumor.
As the most malignant primary central nervous systems tumors, high grade anaplastic astrocytoma and glioblastoma multiforme respond poorly to contemporary multimodality treatment programs employing surgical resection, radiation therapy and chemotherapy with a median survival of less than one year after initial diagnosis (Pardos, et al., 1997, Cancer Medicine, 1:1471-1514; Brandes, et al., 1996, Cancer Invest. 14:551-559; Finlay, J. L., 1992, Pediatric Neuro-Oncology, 278-297; Pardos, et al., 1998, Sem. Surgical Oncol., 14:88-95). Consequently, the development of effective new agents and novel treatment modalities against these very poor prognosis brain tumors remains a major focal point in translational oncology research.